Long-term Safety Evaluation of INZ-701 in Patients with ENPP1 and ABCC6 Deficiencies: A Follow-up Study

The primary objective of this study is to assess the long-term **safety** of INZ-701 in patients with **ENPP1 Deficiency** and **ABCC6 Deficiency**, which are associated with conditions such as **Pseudoxanthoma Elasticum (PXE)** and **Generalized Arterial Calcification of Infancy (GACI)**. Evaluating the safety profile of INZ-701 over an extended period is clinically relevant as it provides critical information on the potential risks and benefits of long-term treatment in these rare genetic disorders.

Secondary objectives include:

• To confirm drug levels of INZ-701 with long-term use, ensuring consistent therapeutic exposure.
• To assess the effect of long-term INZ-701 treatment on plasma **PPi** concentrations, which may provide insights into the drug's mechanism of action and its impact on disease pathology.

The clinical trial involves a total of **186 participants** diagnosed with conditions such as **Pseudoxanthoma elasticum (PXE)**, Generalized Arterial Calcification of Infancy (GACI), Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) Deficiency, and ATP-binding cassette sub-family C member 6 (ABCC6) Deficiency. The study population includes both male and female subjects, with an age range starting from greater than 1 year. Participants were selected based on their completion of the protocol-required safety and PK/PD and/or efficacy period(s) of a previous INZ-701 clinical study in ENPP1 or ABCC6 Deficiency. The trial includes a vulnerable population, and participants are required to provide informed consent or assent as per local regulations. Lifestyle considerations such as the use of contraception for females of childbearing potential and condom use for sexually active males are mandated during and after the trial period. The selection criteria ensure that participants are capable of completing all aspects of the study as assessed by the investigator.

The clinical trial is designed to evaluate the long-term safety of **INZ-701**, a **recombinant human ectonucleotide pyrophosphatase/phosphodiesterase 1** fused to the Fc fragment of IgG1, in patients with **ENPP1 Deficiency** and **ABCC6 Deficiency**. This is a Phase 4, open-label study, which will follow a non-randomized, single-arm design. The trial is expected to commence on August 1, 2024, and conclude by December 31, 2030. Participants will be administered INZ-701 as a lyophilized powder for preparation for injection, delivered via subcutaneous use. The maximum daily dose is set at 2.4 mg/kg, with a total dose not exceeding 804 mg/kg over the treatment period.

The study will include several key visits: an initial screening visit, regular follow-up visits, and an end-of-study visit. The screening visit will confirm eligibility based on criteria such as age, previous completion of a related INZ-701 study, and informed consent. Follow-up visits will monitor the incidence, frequency, and severity of adverse events, as well as changes in clinical laboratory tests. The end-of-study visit will assess the overall safety profile of INZ-701, including the evaluation of anti-drug antibodies and plasma pharmacokinetic parameters.

Participant involvement is expected to last until the study's conclusion, unless early termination is warranted. Conditions for early termination include the occurrence of serious adverse events, non-compliance with study protocols, or withdrawal of consent. The primary endpoints focus on the safety profile, while secondary endpoints include pharmacokinetic parameters and plasma pyrophosphate concentrations. The trial will adhere to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) guidelines, ensuring rigorous safety and ethical standards throughout the study duration.

The clinical trial involves the administration of **INZ-701**, an experimental medication developed by Inozyme Pharma, Inc. **INZ-701** is a **lyophilized powder** intended for preparation as an injection. The active substance in **INZ-701** is **recombinant human ectonucleotide pyrophosphatase/phosphodiesterase 1 fused to the Fc fragment of IgG1**. This protein-based therapeutic agent is designed for **subcutaneous use**. The dosing regimen for **INZ-701** is specified as a maximum daily dose of 2.4 mg/kg, with a total maximum dose of 804 mg/kg over the course of the treatment period, which extends up to 2344 days. The study aims to evaluate the long-term safety of **INZ-701** in patients with ENPP1 Deficiency and ABCC6 Deficiency.

In this trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus remains solely on the administration of **INZ-701**. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the prescribed regimen. The trial is conducted under the designation of an orphan drug, as indicated by the orphan drug designation number EU/3/18/2049, highlighting its potential use in treating rare conditions.

Efficacy in the clinical trial of INZ-701 for patients with ENPP1 Deficiency and ABCC6 Deficiency will be assessed through secondary endpoints. These include the measurement of INZ-701 plasma pharmacokinetic (PK) parameters, which will be evaluated using immunoassay and enzymatic activity. Additionally, plasma inorganic pyrophosphate (PPi) concentrations will be determined based on a validated assay. These assessments will provide insights into the drug's pharmacological effects and its potential therapeutic benefits in the target population. The collection and analysis of these parameters will be conducted in accordance with the trial's protocol, ensuring the reliability and validity of the efficacy data obtained.